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David Daleke Lab

David_Daleke_Slideshow_TEXT.jpg

Ph.D. Stanford University, 1986

 

Associate Professor of Biochemistry and Molecular Biology

Associate Dean for Academics and Administration, University Graduate School

 

Email:  daleked@indiana.edu

Daleke Lab Website


Office Phone: (812) 855-6902

Lab Phone: (812) 855-6161


 

Research Interests

The generation and maintenance of transmembrane phospholipid asymmetry are essential for the function of biological membranes, yet the mechanism underlying these fundamental processes remains unclear. Our research effort is designed to understand how phospholipids are assembled in biological membranes and how the resulting phospholipid asymmetry is maintained. Phospholipid transporters, or "flippases," such as the recently discovered aminophospholipid translocator, represent an interesting new class of proteins that may play a key role in the assembly and organization of phospholipids in biological membranes. These enzymes require energy in the form of ATP, have strict phospholipid structural requirements, and are unique in their ability to transport lipids across membranes. Our goal is to elucidate the structure, function, and biological significance of these proteins.

Our studies employ a variety of biochemical, biophysical, and spectroscopic methods, including protein chemistry, radiolabel, and fluorescent techniques. Part of our work is directed at purifying the aminophospholipid flippase from human erythrocyte membranes. We have purified an ATPase that bears physical characteristics consistent with its involvement in aminophospholipid transport. Our enzymological studies have shown that this enzyme is specifically simulated by phosphatidylserine, the primary substrate of the aminophospholipid flippase. Once this transporter is reconstituted into model membranes, further biophysical studies of lipid-protein interactions and molecular mechanisms of phospholipid transport will be performed.

Concurrently, we are investigating the role of blood cell membrane structure in cardiovascular disease. Specifically, we are studying the loss of transmembrane phospholipid asymmetry observed in diabetic red blood cells to determine the relationship between the vascular complications associated with diabetes and membrane structural perturbations. Our studies indicate that hyperglycemic treatment of non-diabetic cells duplicates this loss of asymmetry by increasing passive lipid flip-flop, without affecting aminophospholipid flippase activity. Antioxidants suppress this loss of asymmetry, implicating a role for glucose-mediated lipid oxidation. Ongoing studies are designed to determine the mechanism by which lipid oxidation induces membrane lipid scrambling, including studies with animal models of diabetes and human diabetics. In related work, we are studying phospholipid transport in normal and diabetic blood platelets to understand the role of oxidative inhibition of the flippase in aminophospholipid externalization, a process required for normal blood clotting. These studies may lead to the development of new strategies for the treatment and prevention of heart disease.

 

Recent Publications 

Shelley Cook and David L. Daleke, “Substrate Specificity of the Aminophospholipid Flippase,” in Membrane Asymmetry and Transmembrane Motion of Lipids, Philippe Devaux and Andreas Herrmann, Eds., J. Wiley & Sons, Inc., 2012, pp 199-223.

Magdalena Marek, Sigrid Milles, Gabriele Schreiber, David L. Daleke, Gunnar Dittmar, Andreas Herrmann, Peter Müller, and Thomas Güenther Pomorski, “The yeast plasma membrane ABC transporter Aus1: Purification, characterization and effect of lipids on its activity,” Journal of Biological Chemistry 286 (2011) 21835-21843.  PMID: 21521689.

Jennifer A. Meyer, Wasanthi Subasinghe, Anders A. F. Sima, Zachary Keltner, Gavin E. Reid, David Daleke and Dana M. Spence, “Zinc-activated C-peptide Resistance to the Type 2 Diabetic Erythrocyte is Associated with Hyperglycemia-induced Phosphatidylserine Externalization and Reversed by Metformin,” Molecular BioSystems (2009).

David L. Daleke, “Regulation of Phospholipid Asymmetry in the Erythrocyte Membrane,” Current Opinion in Hematology 15 (2008) 191-195. PMID: 18391783.

Smriti and David L. Daleke, “ATP-dependent Transport of Phosphatidylserine Analogs in Human Erythrocytes,” Biochemistry, 46 (2007) 2249-2259. PMID: 17269657.

David L. Daleke, “Phospholipid Flippases”, Journal of Biological Chemistry 282 (2007) 821-825 (invited review). PMID: 17130120.

Jill Paterson, Kathleen Renkema, Maragaret Halleck, Robert Schlegel, Patrick Williamson and David L. Daleke, Lipid Specific Activation of the Murine P4-ATPase Atp8a1 (ATPase II),” Biochemistry 45 (2006) 5367-5376. PMID: 17130120.

Dana M. Niedowicz and David L. Daleke, “The Role of Oxidative Stress in Diabetic Complications,” Cell Biochemistry and Biophysics  43  (2005) 289-330. PMID: 16049352.

Peter R. Hoffmann, Jennifer A. Kench, Andrea Vondracek, Ellen Kruk, David L. Daleke, Michael Jordan, Philippa Marrack, Peter M. Henson, and Valerie A. Fadok,  “Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo.”  J Immunol 174 (2005) 1393-1404. PMID: 15661897.

  • NEWS
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  • EVENTS
  • Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis

    Apr 28th, 2015

    Anirban K Mitra, Assistant Professor of Medical and Molecular Genetics has recently published his research in Oncogene. His study links paracrine signals from the microenvironment to the regulation of a key miRNA - miR-193b - in ovarian cancer cells, which promotes metastatic colonization.

    New link between motor proteins and breast cancer

    Apr 21th, 2015

    Collaborative work between Claire Walczak (Medical Sciences) and Ritu Aneja (Georgia Tech) reveals that overexpression of the mitotic kinesin, HSET, promotes tumor progression.

    American Cancer Society awards Research Scholar Grant to Dr. Heather Hundley

    Apr 21th, 2015

    Heather A. Hundley, Assistant Professor of Biochemistry and Molecular Biology, has been awarded a $775,000 grant from the American Cancer Society to support her project “Mechanisms Regulating RNA Editing at Specific Sites in the Transcriptome.”

    PUBLICATION

    Comparison of MAPK specificity across the ETS transcription factor family identifies a high-affinity ERK interaction required for ERG function in prostate cells

    Selvaraj N, Kedage V, Hollenhorst PC

    ERK signaling regulates the opposing roles of JUN family transcription factors at ETS/AP-1 sites and in cell migration

    Selvaraj N, Budka JA, Ferris MW, Plotnik JP, Hollenhorst PC

    Regulatory mechanisms that control mitotic kinesins

    Yount AL, Zong H, Walczak CE

  • Peter Hollenhorst, PhD

    Aug. 31, 4pm JH 009

    Assistant Professor of Biochemistry and Molecular Biology Medical Sciences Program,
    Indiana University Bloomington, IN

    Lindsey D. Mayo, PhD

    Sept. 14, 4pm JH 009

    Associate Professor of Pediatrics
    Associate Professor of Biochemistry and Molecular Biology Wells Center for Pediatric Research
    Indianapolis, IN

    Charles N. Landen Jr, MD

    Sept. 21, 4pm JH 009

    Associate Professor
    Department of Obstetrics and Gynecology
    University of Virginia Cancer Center

    Qianben Wang, PhD

    Sept. 28, 4pm JH 009

    Associate Professor
    Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center
    College of Medicine the Ohio State University

  • CME conference

    Ethical Decisions for End of Life Care

    Wednesday, Jul 8th

    Shawn Gerber, M.Div.
    BCC Director, Spiritual Care & Chaplaincy IU Health Bloomington
    Bloomington, IN

    Pediatric Trauma

    Friday, Jul 10th

    Yueh Chang Ho, MD
    Assistant Prof. of Radiology
    IUSOM
    Indianapolis, IN

    Carpal Tunnel Syndrome

    Wednesday, Jul 15th

    Otto Wickstrom, MD
    IU Health Southern Indiana Physicians
    Orthopedics & Sports Medicine
    Bloomington, IN

    Personalized Medicine: Challenges to Patients & their Physicians

    Friday, Jul 24th

    Kenneth Cornetta, MD
    IU Dept. of Medical & Molecular Genetics

    The Increasing Complexity of Venous Thromboembolic Disease

    Friday, Jul 31st

    Kenneth Cornetta, MD
    David Hedrick, MD

    Indiana Hemophilia & Thrombosis Center
    Indianapolis, IN

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